Revealing the Mechanims of Elastic Dosage Compensation

Correct balance of gene expression dosage is vital for normal cell function and homeostasis.

Chromosomal copy number variation (CNV) results in imbalance of hundreds of genes in a sweep and is poorly tolerated by the cell.

Indeed, most germline aneuploidies result in early miscarriage, and imbalance of whole chromosomes or large genomic segments are common alterations in cancer and associated with disease progression, severity, and response to treatment.

Interestingly, the X chromosome is remarkable exception in this context, as female cells carry two X copies while male cells cope with one.

My research dissects fundamental mechanisms of gene dosage compensation, i.e. how our cells modulate transcription to resolve gene-dose imbalance.

I will uncover how the X chromosome (present as only one active copy per cell) elastically achieves transcriptional hyperactivation to balance its expression levels relative to the autosomal (diploid) part of the genome. Thanks to recent breakthroughs, my lab is in a unique position to discern this outstanding question.

Intriguingly, recent data reveal that even autosomes may achieve a surprising degree of dosage compensation in response to deletion of whole chromosomes or large genomic segments.

Based on recent paradigm-shifting findings, I will map and dissect mechanisms of autosomal dosage compensation, with the goal to reveal general principles by which some CNVs are tolerated by the cell and others lead to loss of homeostasis and cancer.